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Related Concept Videos

Autophagy01:27

Autophagy

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Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.
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Delivery Pathways to the Lysosome01:36

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Eukaryotic cells use different mechanisms to eliminate toxic waste obsolete and worn-out substances. Lysosomes play a pivotal role in this, and hence, these substances are carried to the lysosome from other parts of the cell and extracellular space through different pathways. The most elaborately studied pathways to the lysosome are the endocytic pathways.
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In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
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Autophagic Cell Death01:18

Autophagic Cell Death

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Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
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PI3K/mTOR/AKT Signaling Pathway01:22

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The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
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The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
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cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

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Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
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siRNA Electroporation to Modulate Autophagy in Herpes Simplex Virus Type 1-Infected Monocyte-Derived Dendritic Cells
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Modified (2'-deoxy)adenosines activate autophagy primarily through AMPK/ULK1-dependent pathway.

Ekaterina A Guseva1, Polina N Kamzeeva2, Sofya Y Sokolskaya3

  • 1Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, 143025 Skolkovo, Russia; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.

Bioorganic & Medicinal Chemistry Letters
|October 3, 2024
PubMed
Summary

Researchers explored novel autophagy activators, finding that specific (2'-deoxy)adenosine derivatives outperform AICAr. These compounds show promise for treating metabolic diseases and cancer by modulating cellular self-digestion, even without direct AMPK activation.

Keywords:
AdenosineAutophagyDNA lesionPhosphateProdrugRNA lesion

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The Lactate Dehydrogenase Sequestration Assay &#8212; A Simple and Reliable Method to Determine Bulk Autophagic Sequestration Activity in Mammalian Cells
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Quantitative Analysis of Autophagy using Advanced 3D Fluorescence Microscopy
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Quantitative Analysis of Autophagy using Advanced 3D Fluorescence Microscopy

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Area of Science:

  • Cellular Biology
  • Biochemistry
  • Molecular Medicine

Background:

  • Autophagy is a crucial cellular process for degrading damaged components, upregulated by energy stress via AMP-dependent protein kinase (AMPK).
  • Autophagy activators are potential therapies for metabolic diseases, neurodegeneration, obesity, and cancer.
  • Current activators like AICAr have off-target effects, necessitating new therapeutic strategies.

Purpose of the Study:

  • To evaluate a series of (2 -deoxy)adenosine derivatives as potential autophagy and mitophagy activators.
  • To compare their efficacy against AICAr and investigate their cellular targets.

Main Methods:

  • Utilized a fluorescent reporter assay to measure autophagy/mitophagy activation.
  • Employed immunoblotting analysis to assess protein levels.
  • Tested compound activity in knockout cell lines for AMPK (ΔAMPK) and SIRT1 (ΔSIRT1).

Main Results:

  • Identified specific (2 -deoxy)adenosine derivatives, including oxidized nucleosides and a phosphate-masked adenosine analog, as potent autophagy activators.
  • These novel compounds demonstrated superior efficacy compared to AICAr.
  • Activity was observed in ΔAMPK and ΔSIRT1 cells, suggesting AMPK is not the sole target.

Conclusions:

  • (2 -deoxy)adenosine derivatives represent a promising class of autophagy activators.
  • The phosphate-masking strategy can enhance the efficacy of these compounds.
  • Further research into non-AMPK-dependent autophagy activation pathways is warranted for therapeutic development.